Clinical studies point to a causal relationship between fetal nicotine exposure via maternal smoking and the risk for becoming a smoker. There is also an inverse relationship between the age of first experience, the likelihood of continued nicotine abuse, and experimentation with other psychoactive drugs. Given the extent to which maternal tobacco use occurs during pregnancy, understanding why children and adolescents initiate and maintain tobacco product use is critical to both prevention and early treatment. So how does fetal exposure alter smoking and tobacco product acceptability and preference behavior? Our novel hypothesis is that fetal nicotine exposure induces developmental changes in olfactory function so as to enhance the preference for nicotine odor and nicotine product odor-associated behaviors (e.g., flavor perception of tobacco products). This, in turn, contributes to the risk of initial nicotine-related behaviors (e.g., smoking, chewing tobacco etc.) and continued adolescent abuse. Our proposition is supported by the chemosensory literature, lessons learned from our studies of fetal ethanol exposure, and strong empirical PRELIMINARY DATA demonstrating that clinically relevant fetal exposure to nicotine results in a tuned behavioral response to nicotine odor in early postnatal animals. Our long-range goal is to understand mechanistically how fetal and adolescent nicotine experience impacts an animal's later chemosensory perception of, and odor-related behavior and acceptance responses to the drug. Applying behavioral and neurophysiologic methods, the objectives of this R21 proposal are to firmly establish a chemosensory-based model. We will determine the relationship between fetal nicotine exposure, early postnatal and adolescent odor-guided responsiveness to and acceptance of nicotine, and olfactory neural function. We will test the hypothesis that fetal nicotine exposure causes an altered unconditioned odor-guided and voluntary acceptance response to nicotine in early postnatal and adolescent animals. We will determine whether, and to what degree: (A) the unconditioned odor responses to nicotine are mediated by a tuned neural response of the olfactory epithelium;(B) voluntary acceptance of nicotine is mediated by the altered behavioral odor response to the drug;(C) the observed effects differ between age groups;and (C) the observed effects differ by gender. The proposed work is innovative: it advances a novel hypothesis for fetal nicotine effects on the initiation and maintenance of human nicotine-related product abuse. Our expected outcomes will provide key insights into the relationship between prenatal nicotine exposure and postnatal behavioral preference and responsiveness to the drug. The results will have a significant impact by advancing our understanding of factors contributing to human nicotine abuse. More generally, our findings will further establish an epigenetic chemosensory mechanism by which maternal patterns of drug use can be transferred to offspring. Thus, the proposal has broad implications for the relationship between maternal patterns of substance abuse, child development, and environmental health and safety. PUBLIC HEALTH RELEVANCE: Prenatal nicotine exposure via maternal smoking behavior can cause behavioral changes such as hyperactivity, impulsivity, and impairments in learning, memory and attention. These behavioral effects are in addition to stunted fetal growth, premature birth, stillbirths and increased mortality of newborn. These observations notwithstanding, there are subtler, yet just as detrimental consequences. Human studies demonstrate: (a) that prenatal exposure through maternal smoking increases the probability of smoking among offspring;and (b) that gestational exposure is an important predictor of adolescent abuse. Yet, there is a significant gap in our knowledge of the underlying antecedent factors contributing to this pattern. Our broadly stated hypothesis is that fetal nicotine experience (the addictive component of cigarette smoke) causes developmental changes in chemosensory function, enhancing the preference for nicotine odor and nicotine product odor-associated behaviors (e.g., flavor perception of tobacco products). These changes, we propose, contribute to the risk of tobacco-related product use and abuse in adolescence because these products "smell and taste better". Our studies are expected to advance and expand our understanding of the factors contributing to the initiation and progression of nicotine-related product abuse. An understanding of these processes will facilitate the development and testing of preventive or therapeutic strategies.